In this application we argue that mechanisms of transition from acute to chronic pain critically depend on brain emotional and motivational learning and memory circuit, namely the properties of the corticostriatal system. This is a radical departure from the classic pain research tradition, which emphasizes mechanisms of nociceptive encoding and representation. We provide human and animal model data consistent with the idea, and propose unraveling underlying mechanisms and translating this information to clinical application by testing a drug treatment strategy for preventing transition to chronic pain We recruit Dr. Surmeier (a world renowned expert on the physiology and reorganization of the striatum) and Dr. Martina (a young scientist with expertise in molecular and electrophysiological studies of the brain), to collaborate with Apkarian on this project, and Drs. Fields and Zubieta act as consultants for the project. In Aim 1 we combine the expertise of the three collaborating labs (Apkarian, Martina, Surmeier) to link large-scale brain imaging outcomes to cellular, molecular, and electrophysiological changes that we predict the corticostriatal undergoes in the transition from peripheral nerve injury to neuropathic pain-like behavior in rodents. In Aim 2 we compare among potential drugs for preventing transition to chronic pain-like behavior in a rat model. In Aim 3 we use the best candidate drug in a human early phase clinical trial, combined with brain imaging, for prevention of transition to chronic pain. The successful completion of the study should dramatically change current notions regarding brain mechanisms of pain chronification, and provide a new concept of treatment strategy for preventing the transition to chronic pain. PUBLIC HEALTH RELEVANCE: This application is based on the idea that brain emotional and motivational learning circuitry is an integral part of the transition from acute to chronic pain. T prove this novel concept in mice and rats we combine brain imaging with cellular, molecular, and electrophysiological assays, to demonstrate the maladaptive reorganization of this system during pain chronification. Based on these observations we then test drug manipulations for preventing transition from acute to chronic pain first in rodents and then in a clinical trial with brain imaging in patients with back pain.